Relationship of neurofibrillary pathology to cerebral amyloid angiopathy in Alzheimer's disease

Abstract

Over 90% of patients with Alzheimer's disease (AD) develop cerebral amyloid angiopathy (CAA). Severe dyshoric CAA, in which amyloid extends into the surrounding brain parenchyma, may be associated with adjacent clustering of tau-immunopositive neurites but the relationship of CAA to neurofibrillary pathology has not been systematically investigated. In the present study this relationship was examined in sections of frontal, temporal and parietal cortex from 25 AD patients with moderate to severe CAA and 26 with mild or absent CAA. We measured immunolabelling of abnormally phosphorylated tau adjacent to A beta-laden and non-A beta-laden arteries and arterioles, and in cortex away from arteries and arterioles. We also analysed the possible influence of APOE genotype on these measurements. There were no significant differences between the lobes in measurements of tau labelling, either around blood vessels or elsewhere in the cortex. However, tau labelling around A beta-laden arteries and arterioles significantly exceeded that around non-A beta-laden blood vessels (P<0.001) and this, in turn was greater than the labelling of cortex away from blood vessels (P<0.001). There was no association between APOE epsilon 4 and the immunolabelling density for tau, whether around amyloid- or non-amyloid-laden arteries and arterioles, or in the cerebral cortex away from these. We propose that both CAA and peri-vascular accumulation of hyperphosphorylated tau may be a consequence of elevated levels of soluble A beta around cortical arteries and arterioles.

Pseudomonas aeruginosa Exotoxin Y Is a Promiscuous Cyclase That Increases Endothelial Tau Phosphorylation and Permeability

“…Interestingly, several reports have detected a perivascular accumulation of hyperphosphorylated Tau in brain specimens from patients with Alzheimer disease (84). In these cases, the origin of Tau is presumed to be neural, although it is not clear whether other cells such as endothelium could also be a source.…”

MRI-visible perivascular space location is associated with Alzheimer's disease independently of amyloid burden

“…As well as being a core neuropathological finding in AD, neurofibrillary tangles have been demonstrated in association with CAA in patients with AD (Jeynes and Provias, 2006), and tau deposits (neurofibrillary tangles and pretangles) have been described in Aβ-related angiitis, an inflammatory form of CAA (Kurian et al, 2012). One study reviewing perivascular hyperphosphorylated tau in patients with AD found higher levels surrounding the CAA affected vessels than the unaffected ones (Williams et al, 2005). Thus it is possible that CAA could impair perivascular drainage, leading to tau aggregation, which could further impair perivascular drainage leading to further tau aggregation and so on (a "feed-forward" loop), with MRI-visible perivascular spaces being the end result (Weller et al, 2009;Love and Miners, 2015).…”

Potential mechanisms and implications for the formation of tau oligomeric strains

“…The relationship between tau and the cerebrovasculature in tauopathies has not been thoroughly investigated, although tau has been shown to accumulate in perivascular areas affected by Aβ deposits in the AD brain(Williams et al , 2005b). Additionally, the tuft-shaped astrocytes commonly found in PSP brain frequently have vascular contact, and tau deposits are located in close proximity to blood vessels(Shibuya et al , 2011).…”